The Pediatric HIV/AIDS Cohort Study (PHACS) was created in 2005 to evaluate the clinical course of perinatally acquired HIV infection among adolescents and pre-adolescents and the consequences of fetal and neonatal exposure to HIV and antiretroviral chemotherapy among a representative cohort of children in the United States. PHACS is comprised of a Scientific Leadership Group (SLG), which is overseen by a Coordinating Center, a Data and Operations Center (DOC), and 22 clinical units (CU). The Department of Epidemiology and the Center for Biostatistics in AIDS Research at the Harvard School of Public Health, Westat, and the Frontier Science Foundation form the PHACS DOC. The DOC collaborates with the SLG to define the PHACS research agenda; provides methodological leadership for the development of all PHACS analytic projects; maintains CU subcontracts and trains and monitors sites in proper procedures for PHACS research; plans and conducts all leadership and full PHACS network meetings; develops HIV- and health- related educational materials and opportunities for the PHACS community; and, supports an active Community Advisory Board. The Adolescent Master Protocol (AMP), a cohort of 450 perinatally HIV-infected adolescents and preadolescents age 7-16 at enrollment, was established to investigate the impact of HIV and ART on organ systems, growth and development, sexual maturation, pubertal development, cognition, emotional development, and socialization; AMP Up was subsequently designed to extend follow-up of AMP participants and other HIV-infected young adults who have reached 18 years of age using a streamlined, mobile-friendly protocol. A drug toxicity surveillance system, Surveillance Monitoring for Anti-Retroviral Toxicities (SMART), has enrolled 3,506 perinatally HIV-exposed, uninfected children to evaluate long-term effects of in-utero ART exposure. In PHACS III, the DOC will continue to carry out the PHACS scientific agenda in an increasing efficient manner, enrolling and following an additional 1,000 newborns into SMARTT and an additional 525 HIV-infected and HIV-exposed, uninfected young adults into AMP Up. Together, HSPH, Westat and Frontier Science bring a long and successful history of providing the scientific and operational leadership required by PHACS, as well as innovative methods to enhance and maximize the efficiency of the PHACS study design, conduct, and analyses. Given our prior experience we are uniquely positioned to continue to provide the scientific/epidemiologic and operational leadership essential to the continued success of PHACS.